2-(2-naphthyl)aziridine

ABSTRACT

WHEREIN R REPRESENTS HYDROGEN, HALOGEN, LOWER ALKYL OR LOWER ALKOXY, R1 REPRESENTS HYDROGEN OR ACYL, R IS POSSIBLY PRESENT ON RING A AND RING A AND B MAY BE AROMATIC OR ALICYCLIC, BEING USEFUL AS A TRANQUILIZER OR ANTIDEPRESSANT, IS PREPARED BY REDUCING THE CORRESPONDING OXIME COMPOUND WITH A METALLIC HYDRIDE COMPLEX IN AN INERT SOLVENT.   1-R1,2-(R-2-NAPHTHYL)-AZIRIDINE   A COMPOUND OF THE FORMULA:

United States Patent 3,586,666 2-(2-NAPHTHYL)AZIRIDINE Keizo Kitahonoki,Ikoma-gun, and Katsumi Kotera, Mishima-gun, Japan, assignors to Shionogi& Co., Ltd., Osaka, Japan No Drawing. Continuation-impart of abandonedapplication Ser. No. 510,046, Nov. 26, 1965. This application Sept. 3,1969, Ser. No. 855,020

Claims priority, application Japan, Nov. 26, 1964, 39/66,755; Aug. 13,1965, 40/49,466 Int. Cl. C07d 23/02 U.S. Cl. 260239 1 Claim ABSTRACT OFTHE DISCLOSURE A compound of the formula:

wherein R represents hydrogen, halogen, lower alkyl or lower alkoxy, Rrepresents hydrogen or acyl, R is possibly present on Ring A and Rings Aand B may be aromatic or alicyclic, being useful as a tranquilizer orantidepressant, is prepared by reducing the corresponding oxime compoundwith a metallic hydride complex in an inert solvent.

This application is a continuation-in-part of US. application Ser. No.510,046, filed Nov. 26, 1965 and now abandoned.

The present invention relates to aziridine compounds. Particularly, itrelates to a compound represented by the formula:

where R represents hydrogen, halogen, lower alkyl or lower alkoxy, Rrepresents hydrogen or acyl, R is possibly present on Ring A and Rings Aand B may be each aromatic or alicyclic, which is useful as atranquilizer or antidepressant. The invention also relates to theproduction of the said compound.

Accordingly, a basic object of the present invention is to embody novelaziridine compounds (I). Another ob ject of the invention is to embodyaziridine compounds (I) useful as a tranquilizer, or antidepressant. Afurther object of this invention is to embody a process for theproduction of the aziridine compounds (I). These and other objects willbe apparent to those conversant with the appurtenant art from thefollowing description of the general class of compounds and the severalspecific examples and methods of obtaining them presented.

According to the present invention, the said aziridine compound (I) canbe prepared by reducing an oxime compound represented by the formula:

3,586,666 Patented June 22, 1971 Rings A and B may be aromatic oralicyclic with a metallic hydride complex in an inert solvent. In theabove Formula II, R involves hydrogen, halogen (e.g. chlorine, bromine,iodine), lower alkyl (e.g. methyl, isopropyl, nbutyl) or lower alkoxy(e.g. isopropoxy, methoxy n-pentoxy, ethoxy) which is possibly presentin any of 5-position to 8-position on Ring A. Examples of thesubstituent on the oxime group are lower alkyl (e.g. ethyl, nbutyl,methyl), lower alkanoyl (e.g. acetyl, isopropionyl), aryloyl (e.g.benzoyl, substituted benzoyl), lower alkoxycarbonyl (e.g.ethoxycarbonyl, methoxycarbonyl) and sulfonyl (e.g. toluenesulfonyl,benzenesulfonyl, ethanesulfonyl). These substituents can be connected tothe oxime group by ethereal bonding or ester bonding. The said startingmaterial involves illustratively;

1- 2-naphthyl l -hydroxyiminoethane, 6-acetyltetralin oxime,

Z-acetyl-6-methoxytetralin oxime,

l- (6-chloro-2-naphthyl -1-hydroxyiminoethane, and 2- Z-naphthyll-hydroxyiminoethane.

The starting oxime compound (II) can be prepared in a per seconventional manner such as by reacting a carbonyl compound withhydroxylamine hydrochloride in the presence of pyridine.

As the metallic hydride complex, there are exemplified lithium aluminumhydride, magnesium aluminum hydride and sodium aluminum hydride. Thereduction can be carried out in the range of temperature from 15 C. tothe boiling point of the solvent used in an inert solvent such as ether,tetrahydrofuran, diglyme or tetrahydropyran, when needed, in thepresence of a basic adjuvant such as tert-pentylamine, n-propylarnine,sec-octylamine, diethylamine, N-ethyl n propylaniine,N-methyl-n-butylamine, pyrrolidine, piperazine, N-methyl benzylamine orN-ethyl-fl-phenylethylamine. The resultant crude aziridine compound canbe purified in a per se conventional separating procedure such as byrecrystallization, columnar chromatography, thin layer chromatography orgas phase chromatography. The thus obtained aziridine compound (I) (R=hydrogen) can be, when required, converted into a suitable derivativesuch as acylate for the purpose of separation, isolation, purificationor manufacture of a medicinal. Examples of the acylating reagent are:isocyanate (e.g. phenylisocyanate, p-nitrophenylisocyanate),isothiocyanate (e.g. p-nitrophenylisothiocyanate), dialkyl pyrocarbonate(e.g. diethyl pyrocarbonate, dimethyl pyrocarbonate), aryloyl halide(e.g. p-nitrobenzoyl chloride, benzoyl chloride) and alkylphenoxycarbonate (e.g. ethyl p-nitrophenoxycarbonate, methyl2,4-dinitrophenoxycarbonate). The acylation can be carried out in a perse conventional manner, for instance, under cooling, at room temperatureor under heating in an inert solvent such as water, alcohols, ethers,benzene, toluene, dioxane, diglyme, tetrahydrofuran or tetrahydropyran.In practice, the reagent and solvent must be selected suitably accordingto the object of the acylation. Illustrative examples of acylates in theN-position of the aziridine ring are phenylcarbamoyl compound,p-nitrophenylcarbamoyl compound, phenylthiocarbamoyl compound,p-nitrobenzoyl compound, ethoxycarbonyl compound and methoxycarbonylcompound.

The thus-produced aziridine compounds (I) involve illustratively;

Z-(Z-naphthyl)aziridine, l-ethoxycarbonyl-Z- Z-naphthyl) aziridine, 6-Z-aziridinyl) tetralin,

6-[ l- (p-nitrobenzoyl) aziridin-2-yl1tetralin,2-(6-chloro-2-naphthyl)aziridine, 2-(2-aziridinyl) -6-methoxytetralin,and l-phenylcarbamoyl-Z- Z-naphthyl aziridine.

TABLE 1 Chlor- 2-(2-naph- Chlorproma- Proclilorthyl)aziridiaze- Testcompound zine perazine dine poxide Potentiating narcosis 1 1. 1 7. 1 14.4 17. 4 Hypothermic activity 2 1. 5 10. 4 10. 2 50 Traction test 3 2. 523. 5 19. 7 20 Conditioned reflex 4 1-2 1-2 2-4 5-10 Antiemetic activity5 1. 63 0. 44 1.85 Cataleptic activity 6 23. 4 67 1 Potentiatingnarcosis is observed by administering a test compound subcutaneously tomice and after 10 minutes administering 35 mg./kg.

of sodium thiopental intravenously to the mice and examining the extentof narcosis over 10 minutes. It is shown by ED50 mg./kg. [Gairudtz Arch.t. exp. u. Pharmacol, vol. 164, 118 (1032)].

Hypothermic activity is observed by administering a test compoundsubcutaneously to mice and after 90 minutes examining the fall of bodytemperature over 3 C. and it is shown by ED mg./kg. [Lessin et al. Brit.J. Pharmacol., 12, 245-250 (1957)].

3 Traction test is observed by administering a test compound to mice andafter 90 minutes examining the inhibition of grip strength action inless than 10 seconds, and it is shown by EDao mg./kg. [Courvoisier etal.: Psychotropic Drugs, 373 (1957)].

4 Condition reflex is observed by administering a test compoundsubcutaneously to rats and examining Siedmans avoidance, and it isrepresentefi by an effective dose (mg/kg.) [Siedmanz Science, 118,157-158 Antiemetic activity is observed by administering a test compoundsubcutaneously to dogs, and after 90 minutes administering 0.03 mg./kg.of apomorphine subcutaneously to the dogs and examining [or vomitingaction and it is shown by ED lug/kg. [Freedmanz Science, 124, 264 265(1956)].

Cataleptic activity is observed by administering a test compoundsubcutaneously to rats and after 120 minutes examining the extent ofcatalepsy over 30 seconds while preserving rat legs on four corks, andit is shown by EDso mgJkg. [Winth et al.: Arch. iut.P11armacody, 115, 131 (1958)].

Note: Acute toxicity (LDso) is determined as follows: A test compound isapplied subcutaneously to mice in difterent single doses. For each dosemice are used, their weight ranging from 15 to 17 grams. The mice areobserved for 24 hours after the administration of the compound. The LDsurepresents the amount of the compound which is eXpected to kill half thenumber of mice treated. This is calculated by graphic interpolation fromtwo doses actually used, on of which kills less than half and the othermore than halt the number of mice treated (Schleicher and Schullprobability graphic paper 298 V is used for the graphic interpolation).

Further, acute toxicity of 2-(2-naphthyl)aziridine is as follows: LD 180mg./kg., by subcutaneous administration to rats.

Presently-preferred and practical embodiments of the present inventionare illustratively shown by the following examples. The temperatures areset forth in degree centigrade.

EXAMPLE 1 To a suspension of lithium aluminum hydride (1.741 g.) intetrahydrofuran ml.), there is added dropwise a solution of1-(2-naphthyl)-l-hydroxyiminoethane (2.092 g.) in tetrahydrofuran (50ml.) with cooling, and the resultant mixture is refluxed for 4 hours,chilled below 5 C., mixed with a small amount of water to decompose theexcess of lithium aluminum hydride and filtered. The insoluble part iswashed with ether. The filtrate is combined with the ethereal washings,the mixture is dried over potassium carbonate, and the solvent isevaporated. The residue is purified by passing through an alumina columnto give 2-(2-naphthyl)aziridine (309 mg.) as crystals melting at 102.5to 103.5 C.

To a solution of 2-(2-naphthyl)aziridine (1.006 g.) in ether (20 ml.),there is added a solution of diethyl pyrocarbonate (1.162 g.) in ether(5 ml.). The resultant mixture is allowed to stand at room temperaturefor 4 hours. After evaporation. of the ether, the residue is distilledto give 1-ethoxycarbonyl-2-(Z-naphthyl)aziridine (1.118 g.) as an oilboiling at to 132 C./0.15 mm./ Hg.

EXAMPLE 2 To a suspension of lithium aluminum hydride (4.4 g.) intetrahydrofuran (100 ml.), there is added dropwise a solution ofdiethylamine (8.5 g.) in tetrahydrofuran (10 ml.) and the resultantmixture is stirred for an hour. A solution of 6-acetyl tetralin oxime(5.0 g.) in tetrahydrofuran (50 ml.) is added dropwise to the mixture,which is refluxed for 5 hours. The reaction mixture is mixed with asmall amount of water to decompose the excess of lithium aluminumhydride and filtered. The insoluble part is washed with ether. Thefiltrate is combined with the ethereal washings, dried over potassiumcarbonate and the solvent is evaporated to give an oily residue (4.5g.). The residue is purified by passing through an alumina column togive 6 (2-aziridinyl)tetralin (2.914 g.) as a colorless oil boiling at135 to 136 C./5 mm. Hg.

The product is treated with p-nitrobenzoyl chloride to give6-[l-(p-nitrobenzoyl)aziridin-2-yl1tetralin as crystals melting at 111to 112 C.

EXAMPLE 3 A solution of l-(6-chloro-2-naphthyl)-l-hydroxyiminoethane(2.09 g.), N-methyl-n-butylamine (3.2 g.) and lithium aluminum hydride(1.4 g.) in tetrahydrofuran (112 ml.) is refluxed for an hour, and thereaction mixture is mixed with a small amount of water and filtered. Thefiltrate is evaporated under reduced pressure and the residue ispurified by passing through an alumina column to give2-(6-chloro-2-naphthyl) aziridine as crystals melting at 147 to 148 C.The yield is 51%.

EXAMPLE 4 A solution of 2-(Z-naphthyl)-l-hydroxyiminoethane (93 mg),N-methyl-n-butylamine (130 mg.) and lithium aluminum hydride (57 mg.) intetrahydrofuran (5 ml.) is heated at 60 C. for 4 hours in a closed tube,and the reaction mixture is mixed with a small amount of water todecompose the excess of lithium aluminum hydride. The mixture isfiltered, and the filtrate is chromatographed in gas phase. There isobtained 2-(2-naphthyl)aziridine as crystals melting at 102.5 to 103.5C. The yield is 73%.

The product is treated with phenylisocyanate in ether to give1-phenylcarbamoyl-2-(2-naphthyl)aziridine as crystals melting at to 146C.

What is claimed is:

1. The compound 2-(2-naphthyl)aziridine.

References Cited Gembitskii et al.: Russian Chemical Reviews, vol. 35,p. 116 (1966).

Shionogi & Co., Ltd. Chemical Abstracts, vol. 65, col. 15324-15325(1966).

ALTON D. ROLLINS, Primary Examiner U.S. CL. X.R.

